Hematopoiesis is a complex process for producing multiple and distinct lineages of blood-borne cells throughout the life span of an organism. Hematopoietic stem cells (“HSCs”) represent a subset of undifferentiated cells that resides predominantly in the bone marrow of adult mammals. HSCs, as a population, are capable of self-renewal by maintaining a sufficient number of HSCs within an organism's bone marrow as a reservoir of uncommitted cells that can be further differentiated into various types of new blood cells. Such newly generated blood cells emerge from the bone marrow and enter the circulatory system in order to continuously replace mature/aging circulating blood cell types. The ability of HSCs, as a population, to differentiate and to give rise to cells of multi-lineages is critical for the preservation of an organism.
In order for the maintenance of steady-state hematopoiesis, a balance must be achieved between the rate of self-generation (i.e., for maintaining a steady supply of HSCs) and the rate of differentiation (i.e., for replenishing senescent cells). Hematopoiesis occurs as a developmental continuum in that a given population of HSCs is representative of a heterogeneous mixture of cells, mainly composed of long-term HSCs (“LT-HSCs”) and short-term HSCs (“ST-HSCs”). LT-HSCs are stem cells that have the capacity for self-renewal throughout the life span of an organism. However, ST-HSCs exhibit transient self-renewal properties for a limited period of time (e.g., typically less than 8 weeks in a mouse) prior to undergoing full differentiation. HSCs can differentiate into hematopoietic progenitor cells (“HPCs”) that can further differentiate into clonogenic cells, or cells of a single lineage. For example, the differentiation of common lymphoid progenitors (“CLPs”) can produce T lymphocytes (“T cells”), B lymphocytes (“B cells”), and natural killer cells (“NKs”). The differentiation of common myeloid progenitors (“CMPs”) can generate blood cells of other lineages, including erythrocytes, macrophages, granulocytes, and platelets. The maintenance of mature blood-borne cells in the peripheral circulation is critical for various processes, including oxygen delivery and immunological protection.
Bone marrow transplantation (“BMT”) and hematopoietic stem cell transplantation (“HSCT”) can be effective for the treatment of diseases of the blood, diseases of the bone marrow, cancers of the blood, and cancers of the bone marrow, including various types of anemia, leukemia, and immunological disorders. For example, obtaining HSCs by bone marrow harvesting from donors can be technically challenging in that harvesting sufficient material from the bone marrows of donors involves multiple insertions of large needles to obtain sufficient amount of stem cells. Methods for regenerating HSCs can be useful for treating patients affected by various types of disorders, diseases, or cancers that deleteriously affect the number of endogenous HSCs within a patient.